HIV Experts Create the Roadmap for Providing PrEP to Uninfected Individuals to Reduce the Risk of HIV Infection

WASHINGTON, Aug. 24, 2011 /PRNewswire-USNewswire/ -- To stem the
estimated 2.6 million new HIV infections that occur worldwide each
year, more than 200 representatives from the scientific and
HIV/AIDS communities took an important step in assessing the safety
and public health implications of providing antiretroviral drugs to
uninfected men and women exposed to HIV through sexual contact
– a strategy called pre-exposure prophylaxis, or PrEP.

Assembling August 19 at an open public meeting and interactive
webcast convened by the Forum for Collaborative HIV Research, these
researchers, HIV/AIDS advocates, members of industry and
representatives from National Institutes of Health, the Centers for
Disease Control and Prevention (CDC), Food and Drug Administration
(FDA) and state public health departments applied the findings from
a number of large trials to discuss a roadmap for FDA and CDC to
develop guidance on the safe use of PrEP in otherwise healthy
individuals at high risk of acquiring HIV. Held with the
encouragement of FDA, this meeting has important implications for
medical practice in the U.S. because recent data strongly support
the efficacy of antiretroviral intervention for this purpose.

Although FDA has not yet approved PrEP to reduce HIV acquisition
in uninfected individuals, one form of PrEP recently studied for
use in healthy men or in couples where one partner is HIV positive
–a daily pill containing tenofovir plus emtricitabine
(TDF/FTC) – is FDA-approved for the treatment of HIV
infection. In women, studies have also demonstrated the efficacy of
prophylactic treatment with tenofovir applied as a vaginal gel.

"We now have findings from large studies that support a
conclusion that PrEP is effective in gay and bisexual men, who
represent more than half of new HIV infections in the U.S., and
now, there is evidence that PrEP may reduce HIV infection in
heterosexual men and women, the population hardest hit by HIV
worldwide," said Jur Strobos, M.D., Deputy Director of the Forum.
"We must however, apply these promising data to develop workable
strategies that mitigate risk that may be associated with the
prophylactic use of antiretrovirals. These include both medical and
socio-behavioral risk. We must ensure that people at greatest
risk for acquiring HIV receive a comprehensive package of
prevention services, including regular HIV testing, condom
provision, risk reduction counseling and management of other
sexually transmitted infections. The purpose of our meeting was to
help identify what the components of a complete package should
be."

Among the data reviewed at the meeting were results from the
large-scale, multinational iPrEx trial, which found that a daily
dose of TDF/FTC provided at least 44 percent protection to men and
transgender women who have sex with men (MSM). Among those patients
who were most adherent (used TDF/FTC on 90 percent or more of the
days during the trial), HIV risk was reduced by 73 percent.
Reinforcing these findings, a new CDC trial called the TDF2 study,
along with Partners PrEP conducted by researchers at the University
of Washington, showed that PrEP reduced the risk of HIV in 63
percent of the uninfected heterosexual men and women in the study
population. While unsuccessful in demonstrating efficacy for as yet
unknown reasons, data from the FEMPrEP study presented at the
meeting also confirmed that there were minimal if any safety
concerns associated with daily use of the antiretroviral
drugs. As limited studies, none could assess safety problems
that may arise with broader use – the purpose of this
meeting.

Charting the future use of PrEP as a prevention strategy, the
meeting participants considered how FDA's broad authority to
require Risk Evaluation and Mitigation Strategies (REMS) could be
applied to mitigate the risks associated with the scale-up of
prophylactic use of antiretrovirals. The participants focused
on several medical complications associated with use of the TDF/FTC
combination including a potential impairment in renal function in
some patients with long-term use and an early decrease in bone
mineral density that could stabilize over time.

Due to the need for further study of the long-term side effects
of PrEP, the panel recommended that communication plans be
developed for use by clinicians and patients that stress regular
testing of renal function and the panel agreed that additional REMS
measures, such as a Medication Guide, would be helpful to ensure
adequate monitoring of renal complications – a well-known
phenomenon with the use of tenofovir.

Also assessing available data on how tenofovir impacts bone
mineral density and vitamin D levels, the panel concluded that
additional educational materials are required to address these
medical risks, but that the decision to evaluate bone mineral
density should be left to the healthcare provider on a case-by-case
basis.

Other medical issues included handling of depression, frequent
in this population especially during periods of their lives when
PrEP might be most important; risks to infants of women who wish to
get pregnant on PrEP or who are breast-feeding; and
sexually-transmitted infection – which is not treated or
prevented by PrEP.

Targeted physicians for education should be infectious disease
experts, primary care givers including gynecologists, and
physicians who manage sexually transmitted infections even though
the latter have not previously been involved in longitudinal
care.

At the same time, the panel considered the potential for
patients to develop HIV drug resistance to antiretroviral drugs
used for prevention, noting that drug resistance has been well
documented in HIV/AIDS patients on treatment. Considered by some to
be the thorniest issue associated with the scale-up of PrEP,
resistant HIV is more difficult to treat and frequently requires a
more complicated treatment regimen. Moreover, even though the
development of resistance has not been a concern in ongoing PrEP
clinical studies, the panel members agreed that less frequent
testing for HIV seroconversion that is likely upon scale-up may
exacerbate the problem.

Because FDA can require a restricted distribution plan under
REMS, the panelists debated the use of this system for PrEP,
including requiring physician qualification and registration,
pharmacist distribution limitations, and mandatory patient testing
before a refill can be ordered and dispensed. Although restricted
distribution systems have proven effective in reducing the risks
associated with potent teratogens, like thalidomide, or to assure
the appropriate use of narcotics, panel members concluded that a
restricted distribution plan for PrEP could not be successfully
introduced when the same drug combination is available for
treatment and would impose substantial burdens on healthcare
providers and patients. Further, such a system would impair
access to needed preventative therapy.

The panelists also considered the issue of risk compensation.
Risk compensation would be the engagement in higher risk encounters
or lower use of condoms based on the false belief that these
protections are no longer necessary. While existing clinical trial
data suggests that risk behavior reduces and condom use increases
with PrEP, this was a topic that the panelists agreed should be
addressed in demonstration projects.

The panel members recognized that there are a number of
questions that still need to be answered through post-market and
ongoing studies, including the recommended frequency of HIV
testing; continued vigilance in assessing the development of
resistance on scale-up; and the possibility of risk compensation.
Until these findings are available, however, the panel urged the
development of a communications plan that will emphasize the need
and importance of regular testing, counseling, and, for medical
risks, close monitoring.

With regard to testing patients on PreP therapy for HIV
infection, the panelists expressed caution about requiring
complicated testing that may not be available in public health
clinics. In almost all settings, panel members agreed that routine
rapid enzyme-linked immunoassay testing should be sufficient.
Addressing the costs of testing, payors on the panels provided
assurance that, in covered patients, the cost of recommended
quarterly testing will most likely be reimbursed or compensated,
thus reducing the financial barriers to regular testing and to
PrEP. However, panel members urged the development of
mechanisms that will ensure access to regular testing for PrEP
patients without financial resources.

Next Steps

As FDA considers the findings from this public meeting,
conference participants urged healthcare providers and the public
to await further guidance from the CDC and FDA before considering
using PrEP. However, if providers believe that initiating
PrEP is urgent for a specific patient, CDC recommends following the
cautions and procedures previously published for PrEP use in MSM
(http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm?s_cid=mm6003a1_w).

At the same time, CDC recommends that any healthcare provider
considering PrEP be apprised of the following precautions:

PrEP should only be used among individuals who have been
confirmed to be HIV-negative. Initial and regular HIV testing
is critical for anyone considering using PrEP. All
individuals considering PrEP must also be evaluated for other
health conditions that may impact PrEP use.
PrEP should never be seen as the first line of defense against HIV.
It was only shown to be effective in clinical trials when provided
in combination with regular HIV testing, condoms, and other proven
prevention methods.
Taking PrEP daily is critical. No other dosing regimen was
evaluated in these studies.
PrEP must be obtained and used in close collaboration with health
care providers to ensure regular HIV testing, risk reduction and
adherence counseling, and careful safety monitoring. Anyone
considering using PrEP should speak with his or her doctor.
PrEP has only been shown in clinical trials to reduce HIV infection
among heterosexual men and women and among men who have sex with
men. At this time, there are no data on its benefits or risks
among injection drug users.
Because pregnant and breastfeeding women were excluded from
participation in PrEP trials, further evaluation of available data
will be needed before any recommendations can be made regarding the
use of PrEP for women considering conception or in those who are
breastfeeding infants.

As a next step, the Forum for Collaborative HIV Research will post
the webcast early next week and will publish the proceedings of
this public meeting to advance the regulatory agenda. Once
published, the report will be distributed widely to the Forum's
many constituencies –government, industry, patient advocates,
healthcare providers, foundations, health insurers and academia
–with the goal of advancing research on PrEP and driving
public policy.

About the Forum for Collaborative HIV Research

Now part of the University of California (UC), Berkeley School
of Public Health and based in Washington, D.C., the Forum was
founded in 1997 as the outgrowth of a White House initiative which
called for an ongoing collaboration among stakeholders to address
emerging issues in HIV/AIDS and set the research strategy.
Representing government, industry, patient advocates, healthcare
providers, foundations and academia, the Forum is a public/private
partnership that is guided by an Executive Committee that sets the
research agenda. The Forum organizes roundtables and issues reports
on a range of global HIV/AIDS issues, including treatment-related
toxicities, immune-based therapies, health services research,
co-infections, prevention, and the transference of research results
into care. Forum recommendations have changed how clinical trials
are conducted, accelerated the delivery of new classes of drugs,
heightened awareness of TB/HIV co-infection, and helped to spur
national momentum toward universal testing for HIV. http://www.hivforum.org